Progress To investigate the effects of genetic and environmental factors, and their interactions, on respiratory health in adults we have established several high-quality population resources. We have been working with the extramurally funded cohort, the Atherosclerosis Risk in Communities (ARIC) study to examine both genetic and environmental factors in adult respiratory health. The ARIC study is a cohort of 16,000 adults assembled from 1987-1989 in four US communities. ARIC has a wealth of detailed cardiovascular and respiratory phenotypes. We have used the genome wide association genotyping in ARIC to look for novel genes associated with pulmonary function and chronic obstructive pulmonary disease (COPD) in the setting of the CHARGE Consortium. In 2009, we formed a pulmonary function analysis group within the CHARGE consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology) which includes several other cohorts with genome wide association genotyping and pulmonary function data (PMID: 20010835). In our first CHARGE meta-analysis of pulmonary traits, we identified eight novel loci related to pulmonary function. All have now been replicated by other groups. We subsequently developed a collaborated with a European consortium (SpiroMeta) to expand our work. We have published joint consortium papers on pulmonary function (PMID: 21946350) and COPD (PMID: 22837378 ). Again, our findings have been widely replaced. In 2012 we published one of the first papers incorporating interaction into genome wide association studies (PMID: 23284291). In so doing we identified 3 additional novel loci for pulmonary function. We have also published longitudinal analysis of lung function (PMID: 24983941). We identified 6 novel loci for forced vital capacity, a phenotype that we had not examined in our earlier papers (PMID: 24929828). We have also published on the use of targeted sequencing of two of the novel loci that we identified in our first CHARGE publication - HTR4 and ADAM19 (PMID: 24951661). These results suggest that rare variants do not underlie the associations that we identified earlier. We are currently revisiting all three pulmonary function traits using 1000 Genomes imputation in a multi-ethnic setting within our CHARGE group. We are also doing meta-analysis of rare variants in relation to these traits in subjects of European and African ancestry using the exome chip (submitted). We are also involved in analysis of metabolic and whole genome sequencing data in relation to these traits. In the past year we also worked with the CHARGE Epigenetics group to lead an investigation that identified widespread effects of tobacco smoking on methylation in adults (PMID 27651444) which complements our work on the effects of prenatal exposure to a smoking mother. We also played a leading role in work in this group that found that methylation profiles are an excellent biomarker of long-term alcohol intake (PMID 27843151 ) Another population is the NIEHS Sister Study. This NIEHS cohort has enrolled 50,000 sisters of women with breast cancer. I have added nonmalignant respiratory disease questions to the questionnaire with the aim of examining gene-environment interaction in relation to respiratory disease in this cohort as it matures. The cohort is being followed up annually. We found associations between ambient air pollution and development of asthma and wheeze in this cohort (PMID: 25172226) and also with prevalence of chronic bronchitis (submitted).